The effect of interferons on the invasiveness in vitro of human malignant cells derived from Ewing's sarcoma was evaluated. When treated with either crude or homogeneous fibroblast or lymphoblastoid interferon for 6 days, the cells responded by producing type IV collagenase at levels 2-to 10-fold higher than control values. The ability of Ewing's sarcoma cells to invade human amnion connective tissue was also determined. After 6 days of exposure to crude leuckocyte, homogeneous lymphoblastoid or homogenous fibroblast interferon, invasiveness of the treated samples increased 3-, 17- and 22-fold, respectively, relative to that of untreated controls.